Variable number tandem repeats - Their emerging role in sickness and health

Abstract

Understanding the mechanisms regulating tissue specific and stimulus inducible regulation is at the heart of understanding human biology and how this translates to wellbeing, the ageing process, and disease progression. Polymorphic DNA variation is superimposed as an extra layer of complexity in such processes which underpin our individuality and are the focus of personalized medicine. This review focuses on the role and action of repetitive DNA, specifically variable number tandem repeats and SINE-VNTR-Alu domains, highlighting their role in modification of gene structure and gene expression in addition to their polymorphic nature being a genetic modifier of disease risk and progression. Although the literature focuses on their role in disease, it illustrates their potential to be major contributors to normal physiological function. To date, these elements have been under-reported in genomic analysis due to the difficulties in their characterization with short read DNA sequencing methods. However, recent advances in long read sequencing methods should resolve these problems allowing for a greater understanding of their contribution to a host of genomic and functional mechanisms underlying physiology and disease.

Keywords: SVA; VNTR; neurological disease; physiology; transcriptional regulation.

Figure 1.

Mechanisms by which tandem repeat DNA can modify gene expression. Differential regulation at an allele can result either as a result of polymorphic repeat number, SNPs or indels in the repeats, pathogenic expansion of the repeat or in the case of SVAs presence or absence polymorphism. (A color version of this figure is available in the online journal.)

Figure 2.

Illustration of the consensus structure of the non-long terminal repeat retrotransposon SVA element (∼0.7–4 kb). The VNTR and CT elements can both be polymorphic for the number of tandem repeats and individual single repeat elements can also be polymorphic with SNPs and/or indels, and the polyA (A_n) may also be polymorphic in length. The element is flanked by target site duplications (TSD).